Abstract
Methamphetamine is a widely abused drug associated with significant neuroinflammation and neurodegeneration, mainly through the activation of glial cells and neurons in the central nervous system. This study investigates the role of the astrocyte-specific NOD-like receptor family pyrin domain-containing protein 6 (NLRP6) inflammasome in methamphetamine-induced astrocytic pyroptosis and neuroinflammation. Our findings demonstrate that methamphetamine exposure induces NLRP6-dependent pyroptosis, astrocyte activation, and the release of proinflammatory cytokines in mouse primary astrocytes. Gene silencing of NLRP6 reduces methamphetamine-induced pyroptosis and proinflammatory cytokines release. We also identified miR-152 as a critical upstream regulator of NLRP6, which is downregulated in methamphetamine-exposed astrocytes. Overexpression of miR-152 decreases NLRP6 expression, mitigating methamphetamine-induced pyroptosis and inflammation. In vivo and ex vivo studies in methamphetamine-exposed mice confirmed these results and showed that methamphetamine induces anxiety-like, cognitive impairment, and depression-like behavior, further linking astrocyte-specific NLRP6 signaling to methamphetamine-induced neuroinflammation. This study highlights the potential of targeting the NLRP6 inflammasome in astrocytes as a therapeutic approach to alleviate methamphetamine-induced central nervous system pathology. Further research is warranted to explore clinical applications and identify therapeutic targets for methamphetamine-related neurological disorders.